Hydroxytrimethylsilane

Toxicity to reproduction: other studies

Administrative data

Endpoint:

toxicity to reproduction: other studies

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

2007-10-16 to 2007-10-19

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2008

Report date:

2008

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: OECD Guideline 440 (Uterotrophic Bioassay in Rodents: A short-term screening test for oestrogenic properties) draft

Deviations:

no

GLP compliance:

yes

Type of method:

in vivo

Test material

Test material information

Constituent 1

Reference substance name:

Hydroxytrimethylsilane

EC Number:

213-914-1

EC Name:

Hydroxytrimethylsilane

Cas Number:

1066-40-6

Molecular formula:

C3H10OSi

IUPAC Name:

hydroxytrimethylsilane

Test material form:

other: liquid

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, United States
- Age at study initiation: 42 days old
- Weight at study initiation: 248.4 - 312.6
- Fasting period before study: food was not provided during the inhalation exposure
- Housing: individually in a suspended wire-mesh cages
- Diet: Certified rodent diet, ad libitum
- Water: municipal water, ad libitum
- Acclimation period: 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.8-21.7°C
- Humidity (%): 47-61 %
- Air changes (per hr): 10-15 air changes/hour
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

air

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION

- Exposure apparatus: 1000-liter stainless steel and glass, TSE-system, whole body inhalation exposure chamber

- Method of holding animals in test chamber: Animals were individually placed within stainless steel exposure caging specifically designed for use in the TSE-system chambers. Animals were positioned on the top level within each chamber with individual cage assignment rotated daily. The maximum number of animals per chamber did not exceed 5% of the total chamber volume.

- Source and rate of air: Airflow through the chamber inlet port

- Method of conditioning air: Compressed air was passed through a series of filters to remove contaminants. Conditioned building air was passed through a HEPA and activated charcoal filter before delivery to the chamber.

- System of generating vapour: Chamber concentration of vapour were generated using heated stainless steel J-tubes containing stainless steel beads for increased surface area. A Fluid Metering Inc. (FMI) pump was used to deliver liquid of test substance to the J-tube where it was mixed with a constant stream of filtered compressed air for vaporization. The resulting vapour/air mixture was swept into the chamber inlet for further dilution of the targeted exposure concentration. During each exposure, the J-tube temperature was continuously monitored and values were recorded minimum once during each day of vapour generation.

- Temperature, humidity, pressure in air chamber: Temperature and humidity were measured using a TSE-systems sensor. During the exposure, temperature and humidity were continuously monitored with values recorded every 30 min. The chamber temperature and humidity were maintained at 22 +/- 3 °C and 30-70 %, respectively throughout the exposure period. Oxygen was monitored using a TSE-system oxygen meter. During each exposure, oxygen content was continuously monitored with values recorded every 30 minutes. A minimum concentration of 19% was considered acceptable during the exposure period.

- Air flow rate: chamber airflow rate was measured using a mass-flow meter positioned in-line with the chamber supply air.

- Air change rate: The chamber was operated at an airflow rate appropriate for producing 12-15 chamber air changes per hour.

- Method of particle size determination: no data

- Treatment of exhaust air: no data

TEST ATMOSPHERE
- Brief description of analytical method used: Homogeneity was evaluated by sampling different locations within the chamber during generation of target vapour concentrations. The chamber atmosphere was considered acceptable if the location to location variation was within 10 % of the measured concentration at the reference location. The reference location was representative of the normal sample analysis position anticipated during the exposure interval. Test atmosphere monitoring utilized gas chromatographic analysis with flame ionization detector.

- Samples taken from breathing zone: no data

VEHICLE (if applicable)
- Justification for use and choice of vehicle: The stability of the materials in corn oil has been characterised over an 8-day period using scientifically valid methods.
- Lot/batch no. of vehicle (if required): 126K0117

POSITIVE CONTROL:
Positive control article 1: 17α-Ethynyl estradiol (EE)
Positive control article 2: Genistein
Anti-estrogen control: ICI 182, 780

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Concentration verification of the dose solutions (EE, ICI and genistein) was performed prior to the start of dosing. Due to analytical sensitivity limitations, only 1 mg/ml stock solution of EE was analysed. The ICI was quantified in the mixture of EE and ICI. The test article weight was determined pre- and post-exposure. These data, along with the chamber airflow rate and generation time were used to calculate a nominal chamber concentration of test article. Chamber concentrations were evaluated at least once per hour during each exposure.

Duration of treatment / exposure:

6 hours/day

Frequency of treatment:

daily

Duration of test:

3 days

Doses / concentrations

Dose / conc.:

600 ppm (nominal)

Remarks:

600 ppm trimethylsilanol with and without 3 µg/kg bw/day ethynyl estradiol administered subcutaneously

No. of animals per sex per dose:

6

Control animals:

yes

Details on study design:

Dosing began 20 days following surgery. Control groups (1-8) (see Table 1), EE/TMS combined group and TMS groups received subcutaneous doses of corn oil, EE, genistein or EE+ICI for three consecutive days. The volume of the dosing solutions did not exceed 2 ml/kg. The dose was adjusted daily according to body weight. Different injection site was used each day. After subcutaneous injection, the control rats (groups 1-8) were placed in chambers for whole body inhalation exposure to filtered air for 6 hours/ day. Treatment groups (1-10) were placed in 600 ppm TMS chamber for 6 hours/day. On day 4 from the study period all rats were sacrificed by carbon dioxide asphyxiation.

Statistics:

- ANOVA was used for analysis of differences in uterine weights.
- LSMEANS was used to determine statistically significant treatment effects

Results and discussion

Effect levels

Dose descriptor:

NOAEC

Effect level:

> 600 ppm

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Exposure to trimethylsilanol did not elicit either an estrogenic or anti-estrogenic response.

Observed effects

Clinical signs and mortality: no effects
Body weight and weight gain: no effects
Organ weights: no effects
Gross pathology: no effects

Any other information on results incl. tables

CLINICAL SIGNS AND MORTALITY: No test-article related clinical signs of toxicity were observed. All animals survived throughout the study period. 
BODY WEIGHT AND WEIGHT GAIN: No treatment-related effects on body weight were noted. 
ORGAN WEIGHTS: Treatment with EE and genistein resulted in increase in uterine weight. EE induced a statistically significantly dose-responsive increase in the uterine weight. Genistein also increased the uterine weight, however statistical significance was achieved only by the high-dose. The ICI antagonist blocked the expected EE increase in uterine weight. Exposure to 600 ppm TMS did not induce a statistically significant increase in uterine weight. TMS also had no effect on the EE-induced increase in uterine weigh. 

Applicant's summary and conclusion

Conclusions:

In the uterotrophic assay the test material, trimethylsilanol, did not elicit estrogenic or anti-estrogenic responses after whole body inhalation exposure for 6 hours per day for 3 consecutive days.